The ovarian/menstrual cycle is a complex event characterized by two distinct phases, namely the estrogen rich follicular phase and, after ovulation, the progesterone rich luteal phase. Each has a duration of approximately 14 days resulting in an intermenstrual interval of about 28 days. The endometrial tissue responds to the changes in hormonal milieu.
The onset of menstruation is the begining of a new menstrual cycle and is counted as day 1. During a span of about 5 to 7 days, the superficial layers of the endometrium, which grew and developed during the antecedent ovarian/menstrual cycle, are sloughed because demise of the corpus luteum in the non-fertile menstrual cycle is associated with a loss of progesterone secretion. Ovarian follicular maturation occurs progressively resulting in a rise in the circulating levels of estrogen, which in turn leads to new endometrial proliferation (i.e. mitogenesis induced by the estrogen), predominantly during the second week of follicular maturation.
The dominant ovarian follicle undergoes ovulation at mid-cycle, generally between menstrual cycle days 12 to 16. The follicle is converted from a predominantly estrogen source to a predominantly progesterone source (the corpus luteum).
Ovulation occurs when the oocyte is potentially competent to achieve fertilization, subsequent development and implantation as an embryo. The increasing level of progesterone in the blood converts the proliferative endometrium to a secretory phase in which the tissue proliferation has promptly abated, leading to the formation of endometrial glands or organs. When the ovulated oocyte is viably fertilized and continues its progressive embryonic cleavage, the secretory endometrium and the conceptus can interact to bring about implantation (nidation), beginning about 6 to 8 days after fertilization.
If an ongoing pregnancy is to be established via implantation, the embryo will attach and burrow into the secretory endometrium and begin to produce human chorionic gonadotropin (hCG). The hCG in turn stimulates extended corpus luteum function, i.e. the progesterone production remains elevated, and menses does not occur in the fertile menstrual cycle. Pregnancy is then established.
Pregnancy may not occur for a variety of reasons including, inter alia, absence of competent sperm, lack of fertilization despite exposure of the oocyte to sperm, lack of a competent embryo to achieve implantation, lack of competant endometrium to support implantation, and ineffective subsequent events of placentation and fetal development.
In the non-fertile menstrual cycle, the waning level of progesterone in the blood causes the endometrial tissue to be sloughed. This starts a subsequent menstrual cycle.
Because endometrial proliferation serves to prepare the uterus for an impending pregnancy, manipulation of hormones and of the uterine environment can provide contraception. For example, estrogens are known to decrease follicle stimulating hormone secretion by feedback inhibition. Under certain circumstances, estrogens can also inhibit luteinizing hormone secretion, once again by negative feedback. Under normal circumstances, the spike of circulating estrogen found just prior to ovulation induces the surge of gonadotropic hormones that occurs just prior to and resulting in ovulation. High doses of estrogen immediately post-coitally also can prevent conception probably due to interference with implantation.
Progestins can also provide contraception. Endogenous progesterone after estrogen is responsible for the progestational changes of the endometrium and the cyclic changes of cells and tissue in the cervix and the vagina. Administration of progestin makes the cervical mucus thick, tenacious and cellular which is believed to impede spermatozoal transport. Administration of progestin also inhibits luteinizing hormone secretion and blocks ovulation in humans.
The most prevalent form of oral contraception is a pill that combines both an estrogen and a progestin, a so-called combined oral contraceptive preparation. Apparently, the progestin acts to block gonadotropin release; the estrogen component provides endometrial control to diminish breakthrough bleeding.
Alternatively, there are contraceptive preparations that comprise progestin only. However, the progestin-only preparations have a more varied spectrum of side effects than do the combined preparations, especially more breakthrough bleeding. As a result, the combined preparations are the preferred oral contraceptives in use today (Sheth et al., Contraception 25:243, 1982).
Antiprogestins (sometimes termed "progesterone antagonists" or "anti-gestagens") are a class of materials that block the progesterone receptor. For example, mifepristone (RU 486) is a progesterone receptor antagonist. RU 486 binds to the progesterone receptor and produces a blockade of the binding of progesterone to its receptor. When administered in the luteal phase of the menstrual cycle, RU 486 induces vaginal bleeding.
Unlike the invention described herein, the prior art has demonstrated either inhibition of the ovulatory menstrual cycle or delayed endometrial maturation. It has been demonstrated in primate models that both a single injection of the antiprogestin RU 486 (5 mg/kg, IM) in the late follicular phase or a once weekly oral RU 486 dose of 25 mg prevented ovulation (Collins et al., J. Clin. Endocrinol. Metab. 1986, 63:1270-1276; Danforth et al., Contraception 1989, 40:195-200).
Using various study protocols which differed in regimen and dose, it has been demonstrated by several groups of investigators that RU 486 inhibits ovulation in women as well (Shoupe et al., Am. J. Obstet. Gynecol. 1987, 157:1421-1426; Liu et al., J. Clin. Endocrinol. Metab. 1987, 65:1135-1140; Luukkainen et al., Fertil. Steril. 1988, 49:961-963).
That RU 486 in low dose administration may exhibit an anti-implantation effect in women has been postulated (Spitz et al., The Endocrinology 1993, 3:1, 58 et seq.). Others have demonstrated an influence of RU 486 on endometrial histology, including delayed endometrial maturation (Batista et al., Am. J. Obstet. Gynecol. 1992, 167:60-65). The invention described herein, which is distinct from the prior art, is based on the inhibition of gamete maturation and the fertilization process. Prior art has not demonstrated any such contraceptive effect.
The inventor has discovered that a sufficiently low dose administration of an antiprogestin functions as a contraceptive, but not based on an anti-nidatory effect. Rather, maturation and/or fertilization of the oocyte is prevented and/or inhibited, unrelated to whether implantation could occur.
It is, accordingly, the object of this invention to provide a new method of preventing or inhibiting normal oocyte fertilization without inhibiting ovulation of a mammal, especially primates. This and other objects of the invention will become apparent to those of ordinary skill in this art from the following description.